Glycosaminoglycans (GAGs) are linear, acidic polysaccharides that exist ubiquitously in nature as residents of the extracellular matrix and at the cell surface of many different organisms of divergent phylogeny (Habuchi, O. (2000) Biochim Biophys Acta 1474, 115–27; Sasisekharan, R., Bulmer, M., Moremen, K. W., Cooney, C. L., and Langer, R. (1993) Proc Natl Acad Sci USA 90, 3660–4). In addition to a structural role, GAGs act as critical modulators of a number of biochemical signaling events (Tumova, S., Woods, A., and Couchman, J. R. (2000) Int J Biochem Cell Biol 32, 269–88) requisite for cell growth and differentiation, cell adhesion and migration, and tissue morphogenesis.
Dermatan sulfate (DS) and chondroitin sulfate (CS) are related glycosaminoglycans (GAGs) that are composed of a disaccharide repeat unit of uronic acid (1→3)-linked to N-acetyl-D-galactosamine (GalNAc). These disaccharide repeats are (1→4)-linked to each other to form polymers of chondroitin sulfate or dermatan sulfate. Epimerization at the C5 position of the uronic acid moiety during the biosynthesis of dermatan sulfate leads to a mixture of L-iduronic and D-glucuronic acid epimers (Ernst, S., Langer, R., Cooney, C. L., and Sasisekharan, R. (1995) Crit. Rev. Biochem. Mol. Biol. 30, 387–444). In addition to C5 epimerization, C4 sulfation of GalNAc is another hallmark modification of the DS backbone. Rare sulfation at the 2-O and 3-O positions of the uronic acid moiety has also been reported (Sugahara, K., Tanaka, Y., Yamada, S., Seno, N., Kitagawa, H., Haslam, S. M., Morris, H. R., and Dell, A. (1996) J. Biol. Chem. 271, 26745–54; Nadanaka, S., and Sugahara, K. (1997) Glycobiology 7, 253–63). CS/DS polysaccharides have been implicated in a variety of biological phenomena ranging from anticoagulation to osteoarthritis (Mascellani, G., Liverani, L., Bianchini, P., Parma, B., Torri, G., Bisio, A., Guerrini, M., and Casu, B. (1993) Biochem. J. 296, 639–48; Achur, R. N., Valiyaveettil, M., Alkhalil, A., Ockenhouse, C. F., and Gowda, D. C. (2000) J. Biol. Chem. 275, 40344–56; and Plaas, A. H., West, L. A., Wong-Palms, S., and Nelson, F. R. (1998) J. Biol. Chem. 273, 12642–9). In fact, specific sequences of highly sulfated dermatan sulfate from a variety of invertebrate and mammalian sources are being pursued as pharmaceutically viable treatments for specific blood coagulation disorders (Monagle, P. et al. (1998) J. Biol. Chem. 273, 33566–71; Gandra, M. et al. (2000) Glycobiology 10, 1333–40; and Vicente, C. P. et al. (2001) Thromb. Haemost. 86, 1215–20). Changes in the dermatan sulfate side chain of the small proteoglycan, decorin, have been observed in human colon cancer (Daidouji, K. et al. (2002) Dig. Dis. Sci. 47, 331–7). And modification of existing GAG sequences by chondroitinase B and chondroitinase AC may inhibit angiogenesis and tumor metastasis (Denholm, E. M. et al. (2001) Eur. J. Pharmacol. 416, 213–21). Overall, the role of GAGs as specific mediators of tumorigenesis and other biological events is an emerging field that offers great potential for the development of novel therapeutics (Shriver, Z. et al. (2002) Trends. Cardiovasc. Med. 12, 71–7; and Liu, D. et al. (2002) Proc. Natl. Acad. Sci. USA 99, 568–73).
Flavobacterium heparinum is a common source for GAG-degrading lyases, producing both the extensively characterized heparin-degrading heparinases (Sasisekharan, R., Venkataraman, G., Godavarti, R., Ernst, S., Cooney, C. L., and Langer, R. (1996) J. Biol. Chem. 271, 3124–31; Shriver, Z., Hu, Y., Pojasek, K., and Sasisekharan, R. (1998) J. Biol. Chem. 273, 22904–12; Pojasek, K., Shriver, Z., Hu, Y., and Sasisekharan, R. (2000) Biochemistry 39, 4012–9; and Gu, K., Linhardt, R. J., Laliberte, M., and Zimmermann, J. (1995) Biochem. J. 312, 569–77), as well as the CS/DS-degrading chondroitinases (Gu, K. et al. (1995) Biochem. J. 312, 569–77). Chondroitinase B is the only member of the chondroitinase family that degrades DS as its sole substrate (Jandik, K. A., Gu, K., and Linhardt, R. J. (1994) Glycobiology 4, 289–96 and Pojasek, K., Shriver, Z., Kiley, P., Venkataraman, G., and Sasisekharan, R. (2001) Biochem. Biophys. Res. Commun. 286, 343–51).